title: Preclinical anticonvulsant and neuroprotective profile of 8319, a non-competitive NMDA antagonist.
abstract: 8319, ((+-)-2-Amino-N-ethyl-alpha-(3-methyl-2-thienyl)benzeneethanamine 2HCl), is a novel compound with the profile of a non-competitive NMDA antagonist. The compound displaced [3H] TCP with high affinity (IC50 = 43 nM), but was inactive at the NMDA, benzodiazepine and GABA sites; in vivo, 8319 showed good efficacy as an anticonvulsant and potential neuroprotective agent. It blocked seizures induced by NMDLA, supramaximal electroshock, pentylenetetrazol (PTZ), picrotoxin, and thiosemicarbazide with ED50's of 1-20 mg/kg ip. As a neuroprotective agent, 8319 (30-100 mg/kg sc) prevented the death of dorsal hippocampal pyramidal cells induced by direct injection of 20 nmol NMDA. At 15 mg/kg ip, the compound was also effective against hippocampal neuronal necrosis induced via bilateral occlusion of the carotid arteries in gerbils. In summary, 8319 is a noncompetitive NMDA antagonist with good anticonvulsant activity and may possess neuroprotective properties useful in the treatment of brain ischemia.
authors.affiliation: Department of Chemical Research, Hoechst-Roussel Pharmaceuticals, Inc., Somerville, NJ 08876.
authors.forename: S
authors.initials: S
authors.lastname: Fielding
authors.forename: J C
authors.initials: JC
authors.lastname: Wilker
authors.forename: J
authors.initials: J
authors.lastname: Chernack
authors.forename: V
authors.initials: V
authors.lastname: Ramirez
authors.forename: C A
authors.initials: CA
authors.lastname: Wilmot
authors.forename: L L
authors.initials: LL
authors.lastname: Martin
authors.forename: J F
authors.initials: JF
authors.lastname: Payack
authors.forename: M L
authors.initials: ML
authors.lastname: Cornfeldt
authors.forename: K A
authors.initials: KA
authors.lastname: Rudolphi
authors.forename: D K
authors.initials: DK
authors.lastname: Rush
mesh_terms: D000814:Aniline Compounds / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D001667:Binding, Competitive; D001927:Brain Diseases / Q000517:prevention & control; D002545:Brain Ischemia / Q000188:drug therapy; D016291:Dizocilpine Maleate / Q000378:metabolism / Q000494:pharmacology; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors* / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D013876:Thiophenes / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D014316:Tritium
chemical_list: D000814:Aniline Compounds; D000927:Anticonvulsants; D013876:Thiophenes; D014316:Tritium; C067557:compound 8319; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate